Amidino derivatives and their use as thrombin inhibitors

a technology of amidino derivatives and inhibitors, which is applied in the direction of phosphorous compound active ingredients, drug compositions, group 5/15 element organic compounds, etc., can solve problems such as thromboembolic diseases

Inactive Publication Date: 2001-04-24
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds of the invention have the advantage that they may be more efficacious, be less toxic, be longer acting, have a broader range of activity, be more potent, produce fewer side effects, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.

Problems solved by technology

It is known that hypercoagulability may lead to thrombo-embolic diseases.

Method used

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  • Amidino derivatives and their use as thrombin inhibitors
  • Amidino derivatives and their use as thrombin inhibitors
  • Amidino derivatives and their use as thrombin inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-{3-[2-(4-Aminoiminomethylphenyl)ethoxy]phenyl}benzenesulfonamide.times.HCl

(i) t-Butyloxycarbonylamino-3-hydroxybenzene

Amino-3-hydroxybenzene (5.46 g; 50 mmol) was dissolved in THF (50 mL) and di-t-butyl dicarbonate (12.0 g; 55 mmol) was added at room temperature. The solution was heated for 2 hours at 60.degree. C., the solvent was evaporated and the residue was dissolved in EtOAc (150 mL). The EtOAc-phase was washed with 2.times.20 mL of 1M KHSO.sub.4, 1.times.20 mL water, 1.times.20 mL brine and then dried (MgSO.sub.4). The solvent was evaporated to give 11.74 g of a colourless oil which was crystallised from CH.sub.2 Cl.sub.2 :MeOH:light petroleum to give 9.1 g (87%) of the sub-title compound as white crystals.

.sup.1 H-NMR (400 MHz; CDCl.sub.3): .delta.7.10-7.15 (bs, 1H), 7.11 (t, 1H), 6.72 (dd, 1H), 6.53 (dd, 1H), 6.50 (bs, 1H), 5.57 (apparent bs, 1H), 1.52 (s, 9H) .sup.13 C-NMR (100 MHz; CDCl.sub.3): .delta.156.4, 152.8, 139.4, 129.9, 110.7, 110.2, 105.9, 80.8, 28.3

(ii) t-But...

example 2

Benzenesulfoniacid-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methyl}-phenyl ester.times.HCl

(i) Benzenesulfonic acid-(3-hydroxy-5-methyl)phenyl ester

Benzenesulfonyl chloride (6.36 g; 36 mmol) was added to a well stirred mixture of 3,5-dihydroxytoluene.times.H.sub.2 O (4.26 g; 30 mmol), saturated aqueous NaHCO.sub.3 (70 mL) and Et.sub.2 O (50 mL) and the mixture was stirred at room temperature for 19 hours. Et.sub.2 O (50 mL) was added and the organic layer was separated, collected and evaporated to give 7.05 g of a powder. The crude material was recrystallized from EtOAc:heptane (30 mL:300 mL) to give 4.36 g (55%) of the sub-title compound.

FAB-MS 265 (M+1).sup.+

.sup.1 H-NMR (400 MHz; CDCl.sub.3): .delta.7.86 (d, 2H), 7.67 (tt, 1H), 7.53 (t, 2H), 6.54 (bs, 1H), 6.38 (bs, 1H), 6.31 (t, 1H), 5.02 (s, 1H, OH), 2.21 (s, 3H)

(ii) Benzenesulfonic acid-{3-[2-(4-cyanophenyl)ethoxy]-5-methyl}phenyl ester

Diethylazodicarboxylate (1.74 g; 10 mmol) was added, over 5 minutes, to a stirred solution o...

example 3

N-{3-[2-(4-Aminoiminomethylphenyl)ethoxyl]phenyl}-2-chlorobenzenesulfonamide.times.HOAc

(i) Nitro-3-[2-(4-cyanophenyl)ethoxy]benzene

Triphenylphosphine (11.3 g; 43.1 mmol) and diethylazodicarboxylate (7.5 g; 43 mmol) were dissolved in THF (250 mL) under nitrogen at 0.degree. C. After 5 minutes, 3-nitrophenol (5.00 g; 35.9 mmol) and 2-(4-cyanophenyl)ethanol (6.3 g; 43 mmol) were added. The cooling bath was removed and the mixture stirred for 2 days at room temperature. A new batch was prepared as above and the two were combined before work-up. Water was added and the THF was evaporated. The mixture was extracted with EtOAc, and the organic phase was washed with aqueous 0.2M NaOH and brine, dried (Na.sub.2 SO.sub.4) and the solvent removed in vacuo. Purification by flash chromatography (SiO.sub.2 ; toluene) and recrystallization from CH.sub.2 Cl.sub.2 :EtOH afforded 3.07 g (32%) of the sub-title compound.

.sup.1 H NMR (500 MHz; CDCl.sub.3): .delta.7.82 (dd, 1H), 7.61-7.71 (several peaks,...

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Abstract

There is provided compounds of formula I,wherein R1, R2, R3, Y, n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.

Description

This invention relates to novel pharmaceutically useful compounds, in particular competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07C311/21C07C323/60C07C323/00C07C311/29C07C309/00C07C311/00C07C309/73C07D233/84C07D261/00C07D233/00C07D333/00C07D261/16C07D333/34C07F9/53C07F9/00A61K31/155A61K31/18A61K31/216A61K31/255A61K31/27A61K31/275A61K31/381A61K31/4164A61K31/42A61P7/02C07C309/71C07C311/13C07D233/56C07D261/14
CPCC07C309/73C07C311/21C07C311/29C07F9/5304C07D233/84C07D261/16C07D333/34C07C323/60A61P7/02C07C309/71A61K31/18
Inventor ANTONSSON, THOMAS
Owner ASTRAZENECA AB
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